Giuseppe De Luca, MD, PhD Aggregate Professor of Cardiology Chief Interventional Cardiology

1. PRevEntion of cardiac and Vascular pEriprocedural complications in patients undergoiNg coronary angiography or angioplasTy: IntraCoronary Adenosine administration to prevent peRiprocedUral myonecrosiS in elective coronary angioplasty. A prospective double-blind randomized trial (PREVENT – ICARUS) trial. ClinicalTrials.gov NCT01148147 Giuseppe De Luca, MD, PhD Aggregate Professor of Cardiology Chief Interventional Cardiology Eastern Piedmont University Novara

2. I, Giuseppe De Luca Do not have any conflict of interest

3. PERIPROCEDURAL MYONECROSIS / INFARCTION Myocardial ischemia / coronary vasospasm Distal embolization Reperfusion injury Side branch Loss PREVENT-ICARUS

4. Prevention of periprocedural Myonecrosis • Glycoprotein IIb-IIIa • Verapamil • Nitroprussiate • Nicorandil • Adenosine • Distal/proximal protection devices DRUGS PREVENT-ICARUS

5. Adenosine Receptor A1 :Responsible for AV block Receptor A2A: Microcirculation Vasodilatation Receptor A2B: Broncospasm Receptor A3: Inhibiton of neutrophil degranulation PREVENT-ICARUS

6. Pharmacological effects of Adenosine • Inhibition of platelet aggregation and thrombus formation • Inhibition of activation and accumulation of neutrophils, and their adhesion to endothelial cells • Reduction of calcium overloading and formation of Oxigen free radicals • Vasodilatation of microcirculation • Ischemic preconditioning PREVENT-ICARUS

7. Previous trials in elective patients • Desmet et al: Pilot study ADELINE, 28 pts; adenosine ev -> Reduction in CK-MB • Lee et al: Randomized trials with 62 pts; ic Bolus (50 μg) of adenosine before elective angioplasty -> significant reduction in myonecrosis (39% vs 13%) • Limitation • 1) Open label design • 2) Small dimension • 3) Low-dose intracoronary adenosine • 4) No overall difference in periprocedural MI as defined by 3 times increase in CK-MB PREVENT-ICARUS

8. Aim of the Study To evaluate the adjunctive benefits of high-dose intracoronary adenosine administration as compared to placebo to prevent periprocedural myonecrosis in patients undergoing elective coronary angioplasty. PREVENT-ICARUS

9. METHODS This is a single center, double blind randomized trial. Patients undergoing elective coronary angioplasty were randomly assigned (1:1) through sealed envelops to Placebo or Adenosine administrated intracoronary through the guiding catheter. PREVENT-ICARUS

10. Exclusion criteria • Marked Bradycardia (< 40 bpm) • Previous allergy to adenosine • Inability to sign the informed consent • Asthma • Elevated cardiac enzymes (troponin I o CK-MB)

11. METHODS After knowing the treatment arm, a nurse not involved in the revascularization procedure prepared adenosine (diluted to10 ml with 0.9% NaCl solution, at a concentration of 60 ug/ml) or placebo (10 ml 0.9% NaCl solution), both contained in a 10 cc syringe. Study drug (Adenosine) or placebo were administrated intracoronary through the guiding catheter at the dose of 120 ug (2 ml) (right coronary artery) and 180 ug (3 ml) (left coronary artery), respectively. In case of chronically occluded vessel, randomization was performed after initial dilatation, with al least antegrade TIMI 2 flow. Patients were clinically followed from hospital admission up to discharge.

12. Study Endpoints • Primary study endpoint: • Periprocedural increase in troponin I (> 3 times the upper normal limit). • Secondary study endpoints: • Angiographic coronary flow, as evaluated by corrected TIMI frame count; • 2) Increase in Troponin I > 10 times ULN; • 3) Increase in CK-MB mass > 3 times ULN; • 4) Cumulative in-hospital incidence of death, periprocedural MI, urgent target-vessel revascularization. • Safety endpoint: • Incidence of bradycardia and ventricular arrhythmias during study drug administration. PREVENT-ICARUS

13. Study Hypothesis According to an expected 15% absolute reduction (60% relative reduction) in the incidence of periproceduralmyonecrosis with intracoronary adenosine as compared to placebo (from 25 to 10%), with an anticipated two sided test for differences inindependent binomial proportions at the 5.0% and a statistical power of 80%, a total 112 patients per group were needed. In order to avoid any drop out, the enrolment was extended up to 130 patients per group.

14. 260 patients undergoing elective angioplasty 120-180 μg IC Adenosine (N = 130) IC PLACEBO (N = 130) 0 h PCI 6 h Cardiac enzymes 12 h Cardiac enzymes Study Flow Chart Hospital discharge Clinical outcome

15. Patients’ characteristics

16. Patients’ characteristics

17. Angiographic characteristics

18. Procedural characteristics and results

19. Procedural characteristics and results PREVENT-ICARUS

20. Primary End-point Adenosine Placebo p = 0.69 70 67.7 Troponin I > 3 times ULN (%) PREVENT-ICARUS

21. Secondary End-point Adenosine Placebo p = 0.063 54.6 43.1 Troponin I > 10 Times ULN (%) PREVENT-ICARUS

22. Secondary End-point Adenosine Placebo p = 0.55 12.3 10 CK-MB mass > 3 times ULN (%) PREVENT-ICARUS

23. Adenosine Placebo P = 0.21 13 11.4 cTFC (Frames) Secondary End-point PREVENT-ICARUS

24. Secondary End-point Adenosina Placebo p = 0.44 13.1 In-Hospital Death, PeriMI and uTVR(%) 10 p = 0.28 p = 1.0 1.5 0.8 0 0 Morte uTVR MACE PREVENT-ICARUS

25. Safety Profile 13 cases (10%) of transient (2-4 seconds) AV block, clinically irrilevant (p < 0.001 vs placebo). PREVENT-ICARUS

26. CONCLUSIONS Our randomized trial showed that preprocedural intracoronary administration of a single high-dose bolus of adenosine does not provide any benefit in terms of periprocedural myonecrosis in patients undergoing elective coronary angioplasty. PREVENT-ICARUS

27. However beautiful the strategy, you should occasionally look at the results (Winston Churcill)